Pan-Canadian Registry, Pan-System Disease: Rethinking Fontan Pathobiology

I congratulate Roy et al.¹ on establishing CANFON, a national Canadian longitudinal cohort spanning pediatric and adult Fontan patients, at a time when Fontan palliation has extended survival into adulthood. Patients with Fontan circulation invariably develop progressive multiorgan dysfunction—frailty, exercise intolerance, chronic hepatic congestion and fibrosis, renal impairment, lymphatic, and metabolic derangements—yet the unifying mechanisms remain elusive. Echoing the 2019 American Heart Association Statement’s emphasis on Fontan-associated complications, a major knowledge gap persists in identifying shared biochemical abnormalities driving this cascade.

In our own work, we have sought these central derangements. Using untargeted metabolomics in a matched adult Fontan cohort, we identified elevated circulating bile acids (BAs), whose levels correlated with greater frailty, reduced exercise capacity, and abnormal hemodynamics.² These data support a novel link between Fontan hemodynamics, chronic hepatic congestion, gut microbiome alterations, and systemic metabolic abnormality.

We have, in parallel, delineated a Fontan diastolic-dysfunction phenotype that parallels cirrhotic cardiomyopathy.³ In this state, the single ventricle exhibits reduced lusitropic reserve despite preserved resting function, analogous to the impaired chronotropic and diastolic reserve of cirrhotic hearts.

Importantly, these insights are driving new translational efforts. We have launched the “MYSTIC” trial, a pilot randomized, double-blind, crossover study of colesevelam (a nonabsorbed BA sequestrant) in adult Fontan patients.⁴ This trial will test whether reducing enterohepatic BA recirculation can safely lower plasma BA levels and improve hemodynamic/metabolic profiles. Concurrently, we have generated induced pluripotent stem cell lines from patients with Fontan circulation to model cardiac (and subsequently hepatic) cellular dysfunction in vitro.

We believe that CANFON’s comprehensive, lifespan-scale cohort, combined with our focused translational studies, will be critical to uncover the biochemical underpinnings of Fontan-associated multisystem dysfunction. Only a multipronged approach, integrating registry data, metabolomic and cellular modeling, and targeted interventions can finally bridge the gaps identified by the American Heart Association and improve Fontan outcomes. We commend the CANFON authors for this visionary registry and look forward to synergizing registry findings with mechanistic insights from our work, ultimately paving the way for establishing nontransplant therapies to modulate Fontan pathophysiology.